title: Strong CD8+ T cell antigenicity and immunogenicity of large foreign proteins incorporated in HIV-1 VLPs able to induce a Nef-dependent activation/maturation of dendritic cells.
abstract: Virus-like particles (VLPs) are excellent tools for vaccines against pathogens and tumors. They can accommodate foreign polypeptides whose incorporation efficiency and immunogenicity however decrease strongly with the increase of their size. We recently described the CD8(+) T cell immune response against a small foreign antigen (i.e., the 98 amino acid long human papilloma virus E7 protein) incorporated in human immunodeficiency virus (HIV)-1 based VLPs as product of fusion with an HIV-1 Nef mutant (Nef(mut)). Here, we extended our previous investigations by testing the antigenic/immunogenic properties of Nef(mut)-based VLPs incorporating much larger heterologous products, i.e., human hepatitis C virus (HCV) NS3 and influenza virus NP proteins, which are composed of 630 and 498 amino acids, respectively. We observed a remarkable cross-presentation of HCV NS3 in dendritic cells challenged with Nef(mut)-NS3 VLPs, as detected using a NS3 specific CD8(+) T cell clone as well as PBMCs from HCV infected patients. On the other hand, when injected in mice, Nef(mut)-NP VLPs elicited strong anti-NP CD8(+) T cell and CTL immune responses. In addition, we revealed the ability of Nef(mut) incorporated in VLPs to activate and mature primary human immature dendritic cells (iDCs). This phenomenon correlated with the activation of Src tyrosine kinase-related intracellular signaling, and can be transmitted from VLP-challenged to bystander iDCs. Overall, these results prove that Nef(mut)-based VLPs represent a rather flexible platform for the design of innovative CD8(+) T cell vaccines.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sistigu
authors.forename: L
authors.initials: L
authors.lastname: Bracci
authors.forename: M
authors.initials: M
authors.lastname: Valentini
authors.forename: E
authors.initials: E
authors.lastname: Proietti
authors.forename: R
authors.initials: R
authors.lastname: Bona
authors.forename: D R M
authors.initials: DR
authors.lastname: Negri
authors.forename: A R
authors.initials: AR
authors.lastname: Ciccaglione
authors.forename: E
authors.initials: E
authors.lastname: Tritarelli
authors.forename: R
authors.initials: R
authors.lastname: Nisini
authors.forename: M
authors.initials: M
authors.lastname: Equestre
authors.forename: A
authors.initials: A
authors.lastname: Costantino
authors.forename: C
authors.initials: C
authors.lastname: Marcantonio
authors.forename: S M
authors.initials: SM
authors.lastname: Santini
authors.forename: C
authors.initials: C
authors.lastname: Lapenta
authors.forename: S
authors.initials: S
authors.lastname: Donati
authors.forename: P
authors.initials: P
authors.lastname: Tataseo
authors.forename: M
authors.initials: M
authors.lastname: Miceli
authors.forename: A
authors.initials: A
authors.lastname: Cara
authors.forename: M
authors.initials: M
authors.lastname: Federico
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D057809:HEK293 Cells; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D007371:Interferon-gamma; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D058425:Vaccines, Virus-Like Particle; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D019061:src-Family Kinases; C048842:NP protein, Influenza A virus; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C514837:nef protein, Human immunodeficiency virus 1